scholarly journals Ubiquitin-specific protease 8 (USP8/UBPy): a prototypic multidomain deubiquitinating enzyme with pleiotropic functions

2019 ◽  
Vol 47 (6) ◽  
pp. 1867-1879 ◽  
Author(s):  
Almut Dufner ◽  
Klaus-Peter Knobeloch
Keyword(s):  
T Cell ◽  
Protein Modification ◽  
Catalytic Domain ◽  
Protein Complexes ◽  
Specific Protein ◽  
Protein Protein Interaction ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Associated Function ◽  
And Function

Protein modification by ubiquitin is one of the most versatile posttranslational regulations and counteracted by almost 100 deubiquitinating enzymes (DUBs). USP8 was originally identified as a growth regulated ubiquitin-specific protease and is like many other DUBs characterized by its multidomain architecture. Besides the catalytic domain, specific protein–protein interaction modules were characterized which contribute to USP8 substrate recruitment, regulation and targeting to distinct protein complexes. Studies in mice and humans impressively showed the physiological relevance and non-redundant function of USP8 within the context of the whole organism. USP8 knockout (KO) mice exhibit early embryonic lethality while induced deletion in adult animals rapidly causes lethal liver failure. Furthermore, T-cell specific ablation disturbs T-cell development and function resulting in fatal autoimmune inflammatory bowel disease. In human patients, somatic mutations in USP8 were identified as the underlying cause of adrenocorticotropic hormone (ACTH) releasing pituitary adenomas causing Cushing's disease (CD). Here we provide an overview of the versatile molecular, cellular and pathology associated function and regulation of USP8 which appears to depend on specific protein binding partners, substrates and the cellular context.

scholarly journals Ubiquitin Specific Protease 1 Expression and Function in T Cell Immunity

2021 ◽  
pp. ji2100303
Author(s):  
Kyla D. Omilusik ◽  
Marija S. Nadjsombati ◽  
Tomomi M. Yoshida ◽  
Laura A. Shaw ◽  
John Goulding ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
And Function

scholarly journals Hic-5, an adaptor-like nuclear receptor coactivator

2006 ◽  
Vol 4 (1) ◽  
pp. nrs.04019 ◽  
Author(s):  
Marjet D. Heitzer ◽  
Donald B. DeFranco
Keyword(s):  
Nuclear Receptor ◽  
Protein Complexes ◽  
Specific Protein ◽  
Nuclear Receptor Coactivator ◽  
Group Iii ◽  
Protein Protein Interaction ◽  
Direct Modification ◽  
Nuclear Receptor Coactivators ◽  
Multiple Protein ◽  
Receptor Interacting Proteins

In recent years, numerous nuclear receptor-interacting proteins have been identified that influence nuclear transcription through their direct modification of chromatin. Along with coactivators that possess histone acetyltransferase (HAT) or methyltransferase activity, other coactivators that lack recognizable chromatin-modifying activity have been discovered whose mechanism of action is largely unknown. The presence of multiple protein-protein interaction motifs within mechanistically undefined coactivators suggests that they function as adaptor molecules, either recruiting or stabilizing promoter-specific protein complexes. This perspective will focus on a family of nuclear receptor coactivators (i.e., group III LIM domain proteins related to paxillin) that appear to provide a scaffold to stabilize receptor interactions with chromatin-modifying coregulators.

The N-terminal ubiquitin-binding region of ubiquitin-specific protease 28 modulates its deubiquitination function: NMR structural and mechanistic insights

2015 ◽  
Vol 471 (2) ◽  
pp. 155-165 ◽  
Author(s):  
Yi Wen ◽  
Li Shi ◽  
Yiluan Ding ◽  
Rong Cui ◽  
Wen-tian He ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Molecular Mechanism ◽  
Structure And Function ◽  
Binding Region ◽  
Ubiquitin Binding ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
And Function

We have characterized the structure and function of the N-terminal UBR of Usp28 in this study. Our findings are helpful for a better understanding of the underlying molecular mechanism in the control of catalytic activity of DUBs.

scholarly journals A herpesvirus ubiquitin-specific protease is critical for efficient T cell lymphoma formation

2007 ◽  
Vol 104 (50) ◽  
pp. 20025-20030 ◽  
Author(s):  
K. Jarosinski ◽  
L. Kattenhorn ◽  
B. Kaufer ◽  
H. Ploegh ◽  
N. Osterrieder
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Ubiquitin-specific protease 2-45 (Usp2-45) binds to epithelial Na+ channel (ENaC)-ubiquitylating enzyme Nedd4-2

2011 ◽  
Vol 301 (1) ◽  
pp. F189-F196 ◽  
Author(s):  
Benjamin Oberfeld ◽  
Dorothée Ruffieux-Daidié ◽  
Jean-Jacques Vitagliano ◽  
Klaas Martinus Pos ◽  
François Verrey ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Hek293 Cells ◽  
Na Channel ◽  
Xenopus Laevis Oocytes ◽  
Catalytic Core ◽  
Hect Domain ◽  
Ubiquitin Protein Ligase ◽  
Terminal Domain ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Regulation of the epithelial Na+ channel (ENaC) by ubiquitylation is controlled by the activity of two counteracting enzymes, the E3 ubiquitin-protein ligase Nedd4-2 (mouse ortholog of human Nedd4L) and the ubiquitin-specific protease Usp2-45. Previously, Usp2-45 was shown to decrease ubiquitylation and to increase surface function of ENaC in Xenopus laevis oocytes, whereas the splice variant Usp2-69, which has a different N-terminal domain, was inactive toward ENaC. It is shown here that the catalytic core of Usp2 lacking the N-terminal domain has a reduced ability relative to Usp2-45 to enhance ENaC activity in Xenopus oocytes. In contrast, its catalytic activity toward the artificial substrate ubiquitin-AMC is fully maintained. The interaction of Usp2-45 with ENaC exogenously expressed in HEK293 cells was tested by coimmunoprecipitation. The data indicate that different combinations of ENaC subunits, as well as the α-ENaC cytoplasmic N-terminal but not C-terminal domain, coprecipitate with Usp2-45. This interaction is decreased but not abolished when the cytoplasmic ubiquitylation sites of ENaC are mutated. Importantly, coimmunoprecipitation in HEK293 cells and GST pull-down of purified recombinant proteins show that both the catalytic domain and the N-terminal tail of Usp2-45 physically interact with the HECT domain of Nedd4-2. Taken together, the data support the conclusion that Usp2-45 action on ENaC is promoted by various interactions, including through binding to Nedd4-2 that is suggested to position Usp2-45 favorably for ENaC deubiquitylation.

scholarly journals Role of leukemia cell invadosome in extramedullary infiltration

Blood ◽  
2009 ◽  
Vol 114 (14) ◽  
pp. 3008-3017 ◽  
Author(s):  
Michael Stefanidakis ◽  
Katja Karjalainen ◽  
Diana E. Jaalouk ◽  
Carl G. Gahmberg ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Active Sites ◽  
Catalytic Domain ◽  
Protein Complexes ◽  
Phenotypic Diversity ◽  
Specific Binding ◽  
Leukemia Cell ◽  
Specific Protein ◽  
Human Leukemia ◽  
Functional Protein ◽  
Β2 Integrin

Abstract Acute myelogenous leukemias (AMLs) are characterized by medullary and extramedullary invasion. We hypothesized that a supramolecular complex, the leukemia-cell invadosome, which contains certain integrins, matrix metalloproteinases (MMPs), and other as-yet unidentified proteins, is essential for tissue invasion and may be central to the phenotypic diversity observed in the clinic. Here we show that the specific binding of MMP-9 to leukocyte surface β2 integrin is required for pericellular proteolysis and migration of AML-derived cells. An efficient antileukemia effect was obtained by the hexapeptide HFDDDE, a motif of the MMP-9 catalytic domain that mediates integrin binding: HFDDDE prevented proMMP-9 binding, transmigration through a human endothelial cell layer, and extracellular matrix degradation. Notably, the functional protein anchorage between β2 integrin and proMMP-9 described in this study does not involve the enzymatic active sites targeted by known MMP inhibitors. Taken together, our results provide a biochemical working definition for the human leukemia invadosome. Disruption of specific protein complexes within this supramolecular target complex may yield a new class of anti-AML drugs with anti-invasion (rather than or in addition to cytotoxic) attributes.

scholarly journals N-linked glycans confer protein stability and modulate multidrug efflux pump assemblyin Campylobacter jejuni

2019 ◽  
Author(s):  
Sherif Abouelhadid ◽  
John Raynes ◽  
Tam T.T. Bui ◽  
Jon Cuccui ◽  
Brendan W. Wren
Keyword(s):  
Campylobacter Jejuni ◽  
Protein Modification ◽  
Efflux Pump ◽  
Protein Complexes ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Domains Of Life ◽  
Glycosylation Pathway

AbstractIt is now apparent that nearly all bacteria species have at least a single glycosylation system, but the direct effect(s) of these protein post translational modifications are unresolved. In this study, we used the generalN-linked glycosylation pathway fromCampylobacter jejunito investigate the biophysical roles of protein modification on the CmeABC multidrug efflux pump complex. The study reveals the multifunctional role ofN-linked glycans in enhancing protein thermostability, stabilising protein complexes and the promotion of protein-protein interaction. Our findings demonstrate, for the first time, that regardless of glycan diversification among domains of life,N-linked glycans confer a common evolutionary intrinsic role.

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